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Obesity‐associated Hypoxia Contributes to Aberrant Methylation of Genes Implicated in Inflammation and vascular Function
Author(s) -
Ali Mohamed M.,
Naquiallah Dina,
Hassan Chandra,
Masrur Mario,
Bianco Francesco M.,
Frederick Patrice,
Cristoforo Giulianotti,
Gangemi Antonio,
Phillips Shane A.,
Mahmoud Abeer M.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.08921
Subject(s) - medicine , hypoxia (environmental) , endocrinology , reactive oxygen species , adipose tissue , inflammation , dna methylation , methylation , obesity , leptin , gene expression , chemistry , gene , oxygen , biochemistry , organic chemistry
Obesity is a major risk factor for cardiovascular disease. We previously demonstrated an impaired vascular function in obese adults (OB). We now hypothesize a role of obesity‐associated hypoxia in disturbing the methylation/expression of genes involved in inflammation/vascular function. We also propose a mediating role of the hypoxia‐inducible factor, HIF1α and the DNA hydroxymethylase, TET1. Methods We obtained subcutaneous and visceral adipose tissue (AT) biopsies from bariatric patients (n=60; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and non‐obese (NOB) adults having elective surgeries (n=30; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT‐isolated arterioles were tested for vasoreactivity in response to pressure gradients of Δ10‐Δ100 cmH2O. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and methylation/expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF‐α, and IFNγ were measured in the AT. Results Flow‐induced dilation (FID) was 40–50% higher in NOB than OB adults across all pressure gradients (p<0.05). NO production was higher, and ROS generation was lower in OB arterioles compared to NOB. HIF1α and TET1 proteins were 2–4‐fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID, NO, and brachial artery FID (r=0.82, 0.64, 0.91, respectively; p<0.001) and positively with ROS (r=−0.71, p<0.01). Global hydroxymethylation and adipocytokine promoter hypomethylation and increased expression were observed in OB compared to NOB. Conclusion Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines. This conclusion was also supported by invitro mechanistic studies. Support or Funding Information This research was funded by the National Heart, Lung, and Blood Institute (NHLBI), grants K99HL140049 and 4 R00 HL140049‐03 (AM) and HL095701 (S.P.)